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Bilirubin: A Fat Busting Metabolic Hormone?
Author(s) -
Gordon Darren Mikael,
Mizzuri Scott,
McCullumsmith Robert,
Stec David,
Hinds Terry D.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.00243
Subject(s) - bilirubin , chromatin immunoprecipitation , endocrinology , medicine , biology , peroxisome proliferator activated receptor , receptor , chemistry , biochemistry , promoter , gene expression , gene
Obesity is an epidemic in the United States, which has led to an increased prevalence of insulin‐resistant type II diabetes and heart disease, heightening patient morbidity and mortality. Current treatments of obesity are not sufficient, often requiring combinations for beneficial results, and most have the negative side effect of increasing blood pressure. It has been recently shown that bilirubin, a red blood cell metabolite that at very high levels is commonly associated with liver pathology, prevents cardiovascular disease, diabetes, and obesity at modest levels. We have found that bilirubin induces transcriptional activity via the fat‐burning nuclear receptor, peroxisome proliferator‐activated receptor α (PPARα). RNA‐sequencing in HepG2 hepatocytes showed that bilirubin‐induced transcriptome responses that are predominantly PPARα‐dependent (~95%). From our investigations, we were able to demonstrate a preference for binding of bilirubin to PPARα compared to the other PPAR isoforms (gamma and delta). Utilizing a completely new fluorescent technique established by our lab, we found that bilirubin directly binds to the ligand‐binding domain (LBD) of PPARα. As measured by Pamgene Pamstation Nuclear Hormone Receptor (NHR) chip analysis, we also found that bilirubin functions as a ligand for PPARα and induces the recruitment and dissociation of coregulators that regulate gene function. Subsequent chromatin immunoprecipitation assays showed that bilirubin drives PPARα to the promoters of genes involved in mitochondrial respiration, including the uncoupling protein 1 ( Ucp1 ) and carnitine palmitoyltransferase I A ( Cpt1a ). We affirmed that the effect of bilirubin on mitochondrial function, analyzed by oxygen consumption rate (OCR) using Seahorse analysis, was higher in the cells that expressed PPARα, but not PPARg2. These findings aid in defining the role of bilirubin in altering the metabolic function and, more specifically, through the regulation of mitochondrial‐mediated mechanisms. The investigation of the bilirubin‐PPARα axis reveals a newfound position of bilirubin as a metabolic hormone mediating protection from lipid accumulation and subsequent metabolic dysfunction.